The broad long-term goal of this proposal is to identify novel binding partners for cell surface receptors, and to characterize the functions of cell-cell signaling pathways in vertebrate development, particularly the development of neuronal connections. Aim 1 focuses on identification and characterization of novel ligands. The first part of this Aim deals with receptor-like protein tyrosine phosphatases (RPTPs). In previous work, PTP-NP was identified as a transmembrane RPTP expressed in neurons and neuroendocrine cells. In preliminary studies, candidate binding partners for PTP-NP have been identified, and will be characterized further. The second part of Aim 1 deals with the Amyloid Precursor Protein (APP), a cell surface protein which has important roles in Alzheimer's disease but its normal functions are not well understood. Preliminary studies have molecularly identified a family of ligands that bind to APP and two related APP-like proteins, and developmental function of these interactions will be characterized further. Aim 2 proposes to study developmental functions of intracellular proteins that mediate effects of axon guidance receptors, in particular continuing preliminary studies of MAP kinases. Aim 3 is to study mechanisms that regulate axon responsiveness to guidance cues. As developing axons grow past intermediate targets, they must undergo drastic and highly coordinated changes in the way they respond to multiple guidance cues. In preliminary studies, RNA-based mechanisms have been identified that can regulate protein expression in distal axon segments at an intermediate target, and the function of these mechanisms will be further characterized in controlling the development of axonal connections. While this work focuses on basic biology, studies to identify and characterize novel cell-cell signaling molecules may ultimately lead to therapeutic agents for maintenance, repair or regeneration of neural connections. Studies of PTP-NP in Aim 1 are relevant not only to neuronal development, but also to pancreatic beta cells, including the mechanisms that disrupt their function in diabetes. Studies on APP ligands may lead to new strategies to regulate processing of APP, with potential implications for Alzheimer's Disease.